Racemates of 3,3-disubstituted glutarimides such as 3-ethyl-3-(4-aminophenyl)piperidine-2,6-dione (aminoglutethimide) and 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione (rogletimide; also known as pyridoglutethimide, and sometimes described herein as 4-PG) have been shown to be effective for the treatment of hormone-dependent breast cancer; see Smith et al, Lancet ii:646 (1978), and Foster et al, J. Med. Chem. 28:200 (1985). The mode of action of these compounds is considered to be inhibition of the enzyme aromatase that catalyses the formation of estrogens from androgens; thus the compounds inhibit tumours whose growth is promoted by estrogens.
Graves et al, Endocrinology 105:52 (1979), disclose that the (R)-enantiomers of these compounds are much more potent as inhibitors of aromatase than the (S)-enantiomers. Therefore, it is likely that the (R)-enantiomers are essentially the active components in the racemates, and so a process for their preparation is desirable.
The separate enantiomers of aminoglutethimide and rogletimide have been prepared respectively by repeated recrystallisation of tartrate salts, and by using camphor-derived chiral auxiliaries; see Finch et al, Experimentia 31:1002 (1975), and McCague et al. J. Chem. Soc. Perkin Trans. 1:196-8 (1989). Separation has also been accomplished by chromatography on chiral stationary phases based on tartramides or triacylcelluloses. However, these methods are not amenable to economic large-scale working appropriate for the manufacture of the bulk single-enantiomer drug substance.
Since the filing of the above-identified copending application, McCague et al, J. Med. Chem. 35:3699-3704 (1992), disclose that derivatives of rogletimide, including 5-alkyl derivatives, may have improved aromatase inhibition activity. Aromatase inhibition by the enantiomers of aminoglutethimide, rogletimide and also cyclohexylaminoglutethimide, in vitro, is reported by Ogbunude et al, Chirality 6:623-626 (1994).